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WO-2026093987-A1 - BIPHENYL DERIVATIVES USEFUL AS BFL-1 INHIBITORS

WO2026093987A1WO 2026093987 A1WO2026093987 A1WO 2026093987A1WO-2026093987-A1

Abstract

The present invention is directed biphenyl derivatives, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of leukemias, lymphomas and other cancers.

Inventors

  • BRYAN, Marian C
  • HERNANDEZ BRITO, Claudia
  • HUGHES, TERRY V
  • GRANT, EUGENE B
  • COMPTON, Jordan S
  • BIAN, HAIYAN
  • SODANO, Taylor M
  • ROBERTSON, JAMES
  • SVEC, Riley L
  • STRAMBEANU, Iulia I
  • DERATT, Lindsey
  • BERRY, Angela K
  • REIHER, Christopher Anthony
  • WALL, MARK

Assignees

  • JANSSEN PHARMACEUTICA NV

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (20)

  1. What is claimed:
  2. 1. A compound of Formula (I), wherein
  3. wherein
  4. R 1 is selected from the group consisting of
  5. (a) phenyl; wherein the phenyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO 2 , Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C^alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci- 4 alkyl), -C(O)-(Ci- 4 alkyl), -C(O)OH, -C(O)O-(Ci- 4 alkyl), -C(O)-NR A R B , -NR A R B , -(Ci- 4 alkyl)-NR A R B , -NR A -C(O)-(Ci- 3 alkyl), -NH-C(O)-(Ci- 3 alkyl)-NR A R B , -NH-C(O)-(Ci- 3 alkyl)-NH-C(O)-(Ci- 4 alkyl), -CH(CN)-NR A R B , and -CH(CN)-NH-C(O)-(Ci- 4 alkyl);
  6. wherein R A is selected from the group consisting of hydrogen, and Ci-4alkyl; and R B is selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted C1-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);
  7. wherein
  8. b is an integer from 0 to 1;
  9. L 1 is selected from the group consisting of -(Ci-4alkyl)-, -(Ci-4alkyl)-O-, -O-(Ci- 4 alkyl)-, -(Ci- 4 alkyl)-O-(Ci- 4 alkyl)-, -C(O)O-(Ci- 4 alkyl)-, -C(O)-NR D -, -C(O)-NH-(Ci-
  10. 4alkyl)-NR D -SO2-; wherein R D is selected from the group consisting of hydrogen, and C1- 2alkyl;
  11. provided that when L 1 is -C(O)O-(Ci-4alkyl)-, -C(O)-NH-(Ci-4alkyl)-, -C(O)-NH /\ z°\
  12. -C(O)-NH^^, or -C(O)-NH-^ then the -C(O)- portion of L 1 is bound directly to the phenyl;
  13. provided further that when L 1 is -NR D -C(O)-(Ci-4alkyl)-, then the -NR D - portion of L 1 is bound directly to the phenyl;
  14. provided further that when L 1 is -(Ci-4alkyl)-NR D -SO2-, then the -(Ci-4alkyl)-portion of L 1 is bound directly to the phenyl;
  15. R 3 is selected from the group consisting of C3-6cycloalkyl, aryl, and 4 to 10 membered heterocyclyl;
  16. wherein the C3-6cycloalkyl, aryl, or 4 to 10 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl) and -NR E R F ; wherein R E and R F are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  17. c is an integer from 0 to 3;
  18. each R 4 is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci- 4 alkyl), -(Ci- 4 alkyl)-O-(Ci- 4 alkyl), -C(O)-(Ci- 4 alkyl), -C(O)OH, -C(O)O-(Ci- 4 alkyl), -C(O)-NR G R H , -NR G R H , and -(Ci- 4 alkyl)-NR G R H ;
  19. wherein R G is selected from the group consisting of hydrogen, and Ci-4alkyl; and R H is selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);
  20. and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;

Description

BIPHENYL DERIVATIVES USEFUL AS A BFL-1 INHIBITORS Cross-Reference to Related Applications This application claims priority from United States Provisional Application Serial No. 63/714,902 filed November 1, 2024, the content of which is incorporated by reference in its entirety. Field of the Invention The present invention is directed biphenyl derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of leukemias, lymphomas and other cancers. Background of the Invention Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies, from B- or T-cell origin, accounting for about 4% of all malignancies in the US (BIBIKOVA et al., Blood. 2019; 134 (Supplement_1: 2571). Worldwide, diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of NHL, accounting for 30% to 40% of all newly diagnosed cases (SEHN LH & GASCOYNE RD, Blood. 2015;125(1):22-32). DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid). Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (COIFFiER B & Sarkozy C,. Hematology Am Soc Hematol Educ Program. 2016;2016(1):366-378). Less than half of these patients can be cured with stem cell transplantation (GISSELBRECHT et al., J Clin Oncol. 2010; 28(27): 4184-4190), and those who are not cured will typically die from their disease (CRUMP eta/., Blood. 2017; 130(16):1800-1808). Since the best chance for cure is front-line treatment, there have been many attempts to improve upon R CHOP but so far, these treatments have failed to significantly improve outcomes (GOYA., J Clin Oncol. 2017;35(31):3519-3522). Recently, several studies have explored the addition of targeted agents to R CHOP in front-line treatment. Promising signs of activity in some of these studies encourage the further exploration of combinations that may improve cure rate of targeted agents in select patients (CHIAPPELLA et al., Hematological Oncology. 2017;35(S2):419-428 & YOUNES etal., Lancet Oncol. 2014; 15(9): 1019-1026). Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and Waldenstrom macroglobulinemia (WM) are considered largely incurable lymphomas that require therapies throughout the course of disease. Currently, there are limited lines of therapy available for these diseases, and treatments are needed that avoid the use of cytotoxic chemotherapy. Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Disease remission can be achieved with standard induction chemotherapy, but refractory and relapsed disease remains a challenge due to persistence of leukemic stem cells. Patients refractory to salvage therapy are treated palliatively, as current treatment options are extremely limited. These patients have a median survival of 2 months. Therefore, AML represents an unmet medical need with >20,000 new cases per year in the US with 5-year overall survival below 30% (STEIN ET etal., Health Qual Life Outcomes. 2018; 16: 193). In addition, patients with newly diagnosed intermediate or higher-risk myelodysplastic syndrome (MDS) and those who relapse after standard care have a poor prognosis and high risk of progression to AML. Therefore, there is an urgent need for new treatment modalities for relapsed/refractory (R/R) AML and MDS patients, newly diagnosed AML patients ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate/high/very high risk MDS patients. Intrinsic apoptosis (programmed cell death) is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members sequester their pro-apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance will lead to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic fam